The compound, (⃡)1,4-dihydro-2,6-dimethyl-4-(2&#39;-nitrophenyl)-pyridine-3,5-dicarboxylic acid, methyl isobutyl ester, compositions containing same and a method for effecting coronary dilation

ABSTRACT

The invention relates to optically active 1,4-dihydropyridine compounds of Formulas Ia and Ib as defined hereinabove which are effective for influencing circulation. Also included in the invention are compositions containing said optically active compounds and methods for the use of said compounds and compositions.

This is a continuation, of application Ser. No. 718,916, filed Apr. 2,1985 (now abandoned), which is a continuation in part of Ser. No.429,732 filed Sept. 30, 1982 now U.S. Pat. No. 4,510,310 which in turnis a continuation of Ser. No. 181,453 filed Aug. 25, 1980 (nowabandoned).

The present invention relates to new optically active1,4-dihydropyridine compounds, to processes for their production and totheir use as agents which influence the circulation.

It has already been disclosed that certrain 1,4-dihydropyridinederivatives have interesting pharmacological properties and can be used,in particular, as agents which influence the circulation (see F.Bossert, W. Vater, Naturwissenschaften 58, 578 (1971) and DT-OS2,117,571 (German Published Specification corresponding to U.S. Pat. No.3,799,934). All the pharmacologically active 1,4-dihydropyridinederivatives known hitherto are either achiral compounds or racemic formsof chiral compounds.

It is furthermore known that attempts have already been made to resolveracemic forms of chiral, variously substituted 1,4-dihydropyridinederivatives, but the preparation and isolation of pure antipodes has notpreviously been successful (see J. A. Berson and E. Brown, J. Amer.chem. Soc. 77, 450 (1955). The optically active antipodes of chiral1,4-dihydropyridine derivatives, like those of the preparation processesof the present invention below, are thus new and represent an enrichmentof the art.

According to the present there are provided compounds which are theantipodes of chiral 1,4-dihydropyridinecarboxylic acid esters withdifferent, achiral substituents, of the formula ##STR1## or asalt(particularly (1) a pharmaceutically acceptable acid addition saltor (2) an alkali or-alkaline earth metal salt of those compounds inwhich R₄ is hydrogen)thereof, or are 1,4-dihydropyridinecarboxylic acidesters of the formula ##STR2## in which

R represents an aryl radical or a heterocyclic radical selected fromthienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl,isoquinolyl, indolyl, benzimidazolyl, quinazolyl and quinoxalyl, thearyl radical and the heterocyclic radicals mentioned optionallycontaining 1,2 or 3 identical or different substituents selected fromphenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, dioxyalkylene,halogen, trifluoromethyl, trifluoromethoxy, alkylamino, nitro, cyano,azido, carboxamido, sulphonamido and SO_(m) -alkyl (in which m is 0 or2), R¹ and R³ are identical or different and in each case denote ahydrogen atom, an achiral straight-chain or branched alkyl radical, anaryl radical, or an aralkyl radical, R² denotes a hydrogen atom, anachiral, straight-chain or branched alkyl radical which is optionallyinterrupted by an oxygen atom to form, e.g. an oxa-alkylene chain, anaryl radical or an aralkyl radical, X (a) denotes a nitrile, i.e. cyanoradical, or (b) denotes a group of the formula --COR⁵,

in which

R⁵ denotes an achiral, optionally substituted alkyl, aryl or aralkylradical, or (c) denotes a group of the formula --COOR⁶,

in which

R⁶ denotes an achiral, straight-chain, branched or cyclic, saturated orunsaturated hydrocarbon radical which is optionally interrupted in thechain by oxygen, sulphur (to form, e.g. an oxa- or thia-alkylene chain)or the --SO₂ -- group and which is optionally substituted by halogen,pyridyl, phenyl, phenoxy, phenylthio or phenylsulphonyl, it beingpossible for the phenyl groups in turn to be substituted by halogen,cyano, dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro, or itbeing possible for the hydrocarbon radical to be substituted by an aminogroup, this amino group being substituted by two identical or differentsubstituents selected from alkyl, alkoxyalkyl, aryl and aralkyl, or theamino group being substituted in a manner such that 2 substituents,together with the nitrogen atom, form a 5-membered to 7-membered ring,which optionally contains, as a further hetero-atom, oxygen or sulphur,or a N-alkyl grouping, or (d) denotes a group of the general formula SO₂-R⁷,

in which

R⁷ an archiral straight-chain, branched or cyclic, saturated orunsaturated aliphatic hydrocarbon radical which is optionallyinterrupted in the chain by an oxygen (to form an oxa-alkylene chain,for example, or an oxa-alkylene or an oxa-alkenylene or oxa/alkadienylring and which is optionally substituted by an aryl radical selectedfrom phenyl, phenoxy, phenylthio. phenylsulphonyl and pyridyl or by anamino group, it being possible for the said aryl radicals in turn to beoptionally substituted by halogen, cyano, dialkylamino, alkoxy, alkyl,trifluoromethyl or nitro and the amino group being optionallysubstituted by two identical or different substituents selected fromalkyl, alkoxyalkyl, aryl and aralkyl, or 2 of these substituents, withthe nitrogen atom, optionally forming a 5-membered to 7-membered ring,which optionally contains, as a further hetero-atom, oxygen or sulphur,or the N-alkyl grouping,

or in which

R⁷ denotes an aryl radical which optionally contains 1, 2 or 3 identicalor different substituents selected from alkyl, alkoxy, halogen, cyano,trifluoromethyl, trifluoromethoxy, dialkylamino and nitro, and R⁴independently of R⁶ has any of those meanings given for R⁶, the twosubstituents in the 3-position and 5-position always being differentfrom one another, or ^(*) R⁴ represents a chiral hydrocarbon radicalhaving a single configuration which optionally contains 1, 2 or 3identical or different electron-attracting radicals selected fromnitrile, COO-alkyl, COO-aryl, COO-aralkyl, amino and hydroxyl, the aminoand hydroxyl groups optionally being alkylated, aralkylated, acylated,acetalised or silylated.

As used herein and unless otherwise indicated, "aryl" preferably meansmono- or bi-cyclic carbocyclic aryl; "alkyl" preferably contains 1 to 8especially 1 to 3 or 4 carbon atoms; "alkenyl" and "alkinyl" preferablycontain 2 to 8 especially 2,3 or 4 carbon atoms; "alkylene" preferablycontains 2 to 4 carbon atoms; "dioxyalkylene" preferably contains 2 to 4carbon atoms; "halogen" is preferably chloro or fluoro or bromo'"alkylamino or" dialkylamino preferably contains 1 to 8, especially 1 to3 or 4 carbon atoms in each alkyl group; "aralky" preferably is mono- orbi-cyclic carbocyclic aryl in the aryl portion and 1 to 4, especially 1or 2 carbon atoms in the alkyl portion; a "straight-chain or branchedalkyl radical which is interrupted by an oxygen or sulfur atom" ispreferably oxa- or thina-alkylene or dioxaor dithia-alkylene; "cyclichydrocarbon" is preferably cycloalkyl, cycloalkenyl or cycloalkadienylheaving 3 to 8, especially 5 to 6 ring carbon atoms; and "alkoxyalkyl"preferably contains 1 to 3 or 4 carbon atoms in each alkyl portion.

The compounds of the formula (Ib) according to the invention on the onehand have the same advantageous pharmacological properties as thecompounds of the general formula (Ia), and moreover serve as valuableintermediate products, via which the compounds of the formula (Ia) canbe obtained in a simple manner by transesterification of the chiralsubstituent ^(*) R⁴ (see process variant (c) below).

According to the present invention there is further provided a processfor the production of a compound of the present invention (an antipodeof formula (Ia), or a salt thereof, or a compound of formula (Ib)) inwhich (a) the corresponding racemates of the formula ##STR3## in which

the substituents R, R¹, R², R³, R⁴ and X have the meaning indicatedabove are allowed to interact with a chiral substance, thediastereomeric relationships between the two antipodes of thedihydropyridine and the chiral substance being used to separate theantipodes, or (b) the optically inactive racemic forms of a1,4-dihydropyridinecarboxylic acid of the generalformula ##STR4## inwhich

R, R¹, R², R³ and X have the meanings indicated above, are reacted withan optically active base to give the corresponding diastereomeric saltsand, after separation of the antipodes, the respective salts areconverted into the optically active 1,4-dihydropyridinecarboxylic acidsof the formula ##STR5## in which

R, R¹, R², R³ and X have the meanings indicated above and the opticallyactive acids are then esterified with an alcohol derivative of thegeneral formula

HOR⁴ (V) or ^(*) HOR⁴ (Va) in which

R⁴ and ^(*) R⁴ have the meanings indicated abvve, to give a compound ofthe present invention, or (c) a 1,4-dihydropyridine with an opticallyactive alcohol component in the ester radical -^(*) R⁸, of the formulaformula ##STR6## in which

R, R¹, R², R³ and X have the meanings indicate above and ^(*) R⁸ hasmeaning given for ^(*) R⁴ or denotes a sugar residue which is optionallyperalkylated, acetylated or acetalised, is prepared by one of theprocesses for the synthesis of 1,4-dihydropyridines, using appropriateoptically active starting materials, and the diastereomers obtained bythis prccess are separated by virtue of the two possible differentconfigurations on the C₄ atom of the dihydropyridine ring, the resulting1,4-dihydropyridine with the chiral ester group, of the formula ##STR7##in which

R, R¹, R², R³, ^(*) R⁸ and X have the meaning indicated above, beingtrans-esterified by replacing the chiral ester radicat ^(*) R⁸ by anachiral ester radical R⁴, to give a compound of the formula (Ia), or byanother chiral ester radical ^(*) R⁴, to give a compound of the formula(Ib), or the derivative of formula (VII) of single configuration beinghydrolysed to give a compound of formula (IV) as defined in reactionvariant (b), which is then esterified with an alcohol derivative offormula (V) or (Va) as described in reaction variant (b).

The compounds of the present invention, the optically active1,4-dihydropyridines of the formula (Ia), and their salts, and offormula (Ib)) have valuable pharmacological properties. On the basis oftheir circulation-influencing action, they can be used asantihypertensive agents, as peripheral and cerebral vasodilators and ascoronary therapeutic agents. It has been found that the pharmacologicalaction of the dihydropyridines according to the invention depends on theconfiguration, and that one of the antipodes always has a significantlybetter action than the corresponding racemate. Moreover, it wascompletely unexpected that the pharmacological action is not influencedby the different configurations in the chiral ester radical, but solelyby the configuration of the carbon atom in the 4-position of thedihydropyridine ring. This unexpected finding means that the expert isin a position to use the valuable properties, which are already known,of dihydropyridines more specifically, to prepare new galenicalformulations with a lower content of active compound and to reduceundesired pharmacological side effects. The new optically active1,4-dihydropyridines according to the invention thus represent anenrichment of pharmacy.

Particularly preferred compounds of the present invention are those inwhich

R denotes a phenyl, biphenyl, naphthyl, thienyl, furyl, pyrryl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl,benzimidazolyl, quinazolyl, or quinoxalyl, radical, the rings thereofbeing substituted one or two identical or different substituentsselected from alkyl, cycloalkyl, alkenyl, alkinyl and alkoxy with ineach case up to 7 carbon atoms, trimethylene, tetramethylene,pentamethylene, dioxymethylene, halogen, trifluoromethyl,trifluoromethoxy, nitro, cyano, azido, mono- and di-alkylamino with ineach case 1 to 4 carbon atoms in the alkyl radical, carboxamido,sulphonamido and the radical SO_(m) -alkyl,

in which

m is 0 or 2 and "alkyl" contains 1 to 4 carbon atoms, and R¹ and R³ arein each case identical or different and denote a hydrogen atom or anachiral straight-chain or branched alkyl radical with 1 to 4 carbonatoms, a phenyl radical or a benzyl radical,

R² denotes a hydrogen atom or an achiral strainght-chain or branchedalkyl radical which has 1 to 8 carbon atoms and is optionallyinterrupted in the alkyl chain by an oxygen, or a phenyl or benzylradical,

X (a) denotges a nitrile radical or (b) denotes a group of the generalformula --COR⁵

in which

R⁵ denotes an achiral straight-chain or branched alkyl radical with 1 to4 carbon atoms, phenyl or benzyl, or (c) denotes a group of the generalformula --COOR⁶,

in which

R⁶ denotes an achiral straight-chain, branched or cyclic, saturated orunsaturated hydrocarbon radical which has up to 8 carbon atoms, isoptionally interrupted once in the alkyl chain by oxygen, sulphur or the--SO₂ -- group and is also substituted by fluorine, chlorine, bromine ortrifluoromethyl or by phenyl, phenoxy, phenylthio or phenylsulphonyl,the phenyl radicals in turn being optionally mono-substituted ordisubstituted by fluorine, chlorine, bromine, cyano, nitro ortrifluoromethyl or by alkyl, alkoxy or dialkylamino with in each case 1to 4 carbon atoms in the alkyl and alkoxy radicals, or the hydrocarbonradical is optionally substituted by α-, β- or γ-pyridyl or by an aminogroup, this amino group optionally carrying two identical or differentsubstituents selected from alkyl with 1 to 4 carbon atons, alkoxyalkylwith up to 6 carbon atoms, phenyl, benzyl and phenethyl, or the nitrogenof this amino group, with the substituents, forming a 5-membered to7-membered ring, which optionally contains, as a further hetero-atom, anoxygen or sulphur atom, or an N-alkyl group with 1 to 4 carbon atoms inthe alkyl radical, or (d) denotes a group of the general formula --SO₂--R⁷,

in which

R⁷ denotes an achiral straight-chain, branched or cyclic, saturated orunsaturated aliphatic hydrocarbon radical which has up to 6 carbonatoms, is optionally interrupted in the chain by an oxygen atom and itoptionally substituted by phenyl, phenoxy, phenylthio orphenylsulphonyl, the phenyl radicals mentioned being in turn likewisemonosubstituted or disubstituted by fluorine, chlorine, bromine, cyano,nitro or trifluoromethyl or by alkyl, alkoxy or dialkylamino with ineach case 1 to 4 carbon atoms in the alkyl or alkoxy radicals, or thehydrocarbon radical is substituted by α-, β-or γ-pyridyl or by an aminogroup, this amino group carrying two identical or different substituentsselected from alkyl and alkoxyalkyl with in each case up to 4 carbonatoms, phenyl, benzyl and phenethyl, or the substituents of this aminogroup, with the nitrogen atom, forming a 5-membered to 7-membered ring,which optionally contains, as a further heteroatom, an oxygen or sulphuratom, or a N-alkyl grouping, that alkyl group containing 1 to 3 carbonatoms,

or in which

R⁷ denotes a phenyl radical which is optionally substituted by 1, 2 or 3identical or different substituents selected from nitro, cyano,trifluoromethyl, trifuloromethoxy, fluorine, chlorine, bromine, alkyl,alkoxy and dialkylamino, the alkyl and alkoxy radicals mentionedcontaining, in each case, 1 to 4 carbon atoms, and R⁴ independently ofR⁶, has any of the meanings given for R⁶, the two substituents in the3-position and 5-position always being different from one another, or^(*) R⁴ denotes a chiral, aliphatic hydrocarbon radical having a singleconfiguration and up to 8 carbon atoms and optionally contains 1, 2 or 3identical or different electron-attracting radicals selected fromnitrile, COO-alkyl with 1 to 4 carbon atoms, COO-phenyl, COO-benzyl and-phenethyl, amino and hydroxyl, these amino and hydroxyl groupsoptionally being alkylated, aralkylated, acylated (preferably carboxylicacid acylated), acetalized or silylated, wherein the alkyl, acyl andacetal groups in each case contain up to 6 carbon atoms and the aralkylgroup denotes benzyl or phenethyl

Especially preferred compounds of the present invention are those inwhich

R denotes a phenyl radical which is monosubstituted or disubstituted bynitro, cyano, trifluoromethyl, trifluoromethoxy, fluorine, chlorine,bromine, azido, alkoxy or alkylmercapto with in each case 1 or 2 carbonatoms, or pyridyl, R¹ and R³ are identical or different and in each casedenote a hydrogen atom or an alkyl group with 1 or 2 carbon atoms, R²denotes a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or abenzyl radical, X denotes a nitrile radical, or the group of the generalformula ---COOR⁶,

in which

R⁶ denotes an achiral alkyl radical which has 1 to 6 carbon atoms and isoptionally substituted by an alkoxy group with 1 to 4 carbon atoms, byfluorine or by an amino group, which in turn is monosubstituted by alkylwith 1 to 4 carbon atoms and carries, as the third substituent, anidentical or different alkyl group with 1 to 4 carbon atoms or a benzylradical, and R⁴ denotes an achiral radical having, independently of R⁶,any of the meanings given for R⁶, the two substituents in the 3-positionand 5-position always being different from one another, or ^(*) R⁴represents a chiral hydrocarbon radical having a single configurationwhich is optionally substituted by one or two identical or differentelectron-attracting radicals selected from nitrile, COO-alkyl with 1 or2 carbon atoms, COO-benzyl, amino and hydroxyl, the amino and hydroxylgroups optionally being alkylated by alkyl radicals with 1 or 2 carbonatoms, benzylated, acylated by acyl radicals with 1 to 4 carbon atoms,acetalysed by acetone or benzaldehyde or silylated by trimethylsilyl ortriphenylsilyl.

The process variants (a), (b) and (c) for the production of compounds ofthe present invention are described in more detail, as follows.

Process variant (a)

According to process variant (a), the optically inactive racemic form ofa dihydropyridine derivative of the general formula (II) is allowed tointeract with a chiral substance, the diastereomeric relationshipsleading to resolution into the two optically active antipodes of theformula (Ia). The racemic forms of the 1,4-dihydropyridines of theformula (II) which are used as starting substances for this proccess areknown or they can be prepared by known methods (see DT-OS (GermanPublished Specification) 2,117,571 corresponding to U.S. Pat. No.3,799,934 and DT-OS 2,508,181 corresponding to U.S. Pat. No. 4,044,141).

Examples which may be mentioned are:5-cyano-1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3-carboxylicacid cyclopentyl ester,5-acetyl-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3-carboxylicacid isopropyl ester5-benzoyl-1,4-dihydro-2-methyl-6-phenyl-4-(2'-trifluoromethylphenyl)-pyridine-3-carboxylicacid ethyl ester,5-phenylsulphonyl-1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3-carboxylicacid propyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitro-phenyl)-pyridine-3,5-dicarboxylicacid ethyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-methoxyphenyl)-pyridine-3,5-dicarboxylicacid allyl isopropyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-cyanophenyl)-pyridine-3,5-dicarboxylicacid benzyl isopropyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isobutyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxy-ethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-propxyethyl ester, 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-phenoxyethylester,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid methyl 2,2,2-trifluoro-ethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid cyclopentyl 2,2,2-trifluoroethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2-dimethylaminoethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2-(N-benzyl-N-methyl)-aminoethyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-3-yl)-pyridine-3,5-dicarboxylic acidisopropyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-2-yl)-pyridine-3,5-dicarboxylic acidcyclopentyl 2-methoxyethyl ester,1,4-dihydro-2,6-dimethyl-4-(2-mehylthio-pyrid-3yl)-pyridine-3,5-di-carboxylicacid ethyl methyl ester and1,4-dihydro-2,6-dimethyl-4-(quinol-4-yl)-pyridine-3,5-dicarboxylic acidisopropyl methyl ester.

The optically active adsorbents customarily used in chromatographicseparation processes may be mentioned as preferred chiral substanceswhich can be used for this process variant (a). These adsorbentsinclude, as preferences, variously acylated cellulose derivatives,polymeric, optically active phenylethylamine derivatives and polymericaminoacid derivatives. Depending on the nature of the racemic compoundof the general formula (II) to be resolved, it is, of course, alsopossible to use other optically active adsorbents, such as,

optically active polysaccharides and also those optically activecompounds which are firmly anchored to the surface of an inactivecarrier (see: E. L. Eliel, Stereochemie der Kohlenstoffvebindungen(Stereochemistry of Carbon Compounds), Verlag Chemie (1966) and A. D.Schwanghart, W. Backmann and G. Blaschke, Chem. Ber. . 110, 778 (1977);also see the preceding for further literature).

Possible eluting agents in these preferred chromatographic separationprocesses are any of the inert organic solvents or mixtures thereof.These include, preferences, hydrocarbons, such as, for example,cyclohexane, petroleum ether, benzene or toluene; chlorinatedhydrocarbons, such as, for example, carbon tetrachloride, chloroform ormethylene chloride; ethers, such as, for example, dioxane,tetrahydrofurane or diisopropyl ether; alcohols, such as, for example,ethanol or isopropanol; or ketones and esters, such as, for example,acetone or ethyl acetate.

Process variant b

According to process variant b, the optically inactive racemic form of1,4-dihydropyridinecarboxylic acids of the general formula (III) isreacted with an optically active base and the diastereomeric saltsthereby formed are resolved into the optically active1,4-dihydropyridinecarboxylic acids of the formula (IV), which are thenesterified to give compounds of the formula (I).

The racemic 1,4-dihydropyridinecarboxylic acids of the general formula(III) used as starting substances are known (see: A. Sautin et al.,Khim. Geterotsiklich Soedin, 272 (1978)), or they can be obtained in asimple manner by alkaline hydrolysis of the corresponding1,4-dihydropyridine-3-carboxylic acid 2-cyano-ethyl esters (see: DT-OS(German Published Specification) 2,847,237).

Examples which may be mentioned are5-cyano-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3-carboxylicacid,5-acetyl-1,4dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3-carboxylicacid,5-benzoyl-1,4-dihydro-2-methyl-6-phenyl-4-(2'-trifluoromethylphenyl)-pyridine-3-carboxylicacid,5-phenylsulphonyl-1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3-carboxylicacid,1,4-dihydro-2,6-dimetyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid monomethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid monomethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid monoethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid monoisopropyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid monoisobutyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid monocyclopentyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylicacid monoethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-cyanophenyl)-pyridine-3,5-dicarboxylicacid monobenzyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid mono-(2-methoxyethyl) ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid mono-(2'-propoxyethyl) ester,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid monomethyl ester,4dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylic acidmono-(2,2,2-trifluoroethyl) ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid mono-(2-(N-benzyl-N-methylamino)-ethyl) ester,1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylicacid monoethyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-2-yl)-pyridine-3,5-dicarboxylic acidmonoethyl ester,1,4dihydro-2,6-dimethyl-4-(pyrid-3-yl)-pyridine-3,5dicarboxylic acidmonoethyl ester and 1,4-dihydro-2,6-dimethyl-4-(2-methylthio-pyrid-3-yl)-pyridine-3,5-dicarboxylic acid monoethyl ester.

The optically active bases used for forming the diastereomeric salts areknown (see: S. H. Wilen et al., Tetrahedron 33, 2725 (1977)).

Examples which may be mentioned are: cinchonine, cinchonidine, quinine,quindine, brucine, strychnine, morphine, ephedrine, α-phenylethylamine,α-(2-naphthyl)-ethylamine, menthylamine, amphetamine anddehydroabietylamine.

When the racemic 1,4-dihydropyridinecarboxylic acids of the formula(III) are reacted with one of the abovementioned optically active bases,diastereomeric salts are formed. These differ from one another inrespect of their physical properties and can thus be separated from oneanother with the aid of known methods. Preferred separation processeswhich may be mentioned are recrystallisation from a suitable inertsolvent, separation by thin layer chromatography or columnchromatography or separation by high performance liquid chromatography.

The diastereomeric salts which are separated with the aid of thesemethods and have a single configuration are converted into opticallyactive 1,4-dihydropyridinecarboxylic acids of the formula (IV) by addinginorganic or lower organic acids, for example, hydrochloric acid orhydrobromic acid, dilute sulphuric or phosphoric acid or acetic acid, orwith the aid of ion exchangers.

The optically active acids of the formula (IV), thus obtained arepreferably converted into the correspond optically active esters of theformula (I) by esterification by known methods, for example via thecorresponding carboxlyic acid azolides or by thedicyclohexylcarbodiimide method (see H. A. Staab and W. Rohr, NeuereMethoden der praparativen organischen Chemie (Recent Methods ofPreparative Organic Chemistry), Volume V, page 53 et seq. (1967) and B.Neires and W. Steglich, Angew. Chem. 90, 556 (1978)).

Process variant (c)

Accordding to variant c, a dihydropyridine ester of the formula (VI)which has an optically active alcohol component (--^(*) OR⁸) is firstsynthesised by a customary 1,4-dihydropyridine synthesis. Because of thetwo possible, opposite configurations on the C₄ atom of the1,4-dihydropyridine ring, 2 diastereomers are thereby formed. These areseparated by customary methods and the optically active alcoholcomponent is then optionally replaced by an achiral, optically inactivealcohol component (--OR⁴), so that compounds of the formula (Ia) areformed. The optically active alcohol component --^(*) OR⁸ is optionallyreplaced by a correspondingly chiral, optically active alcohol component--^(*) OR ⁴, so that compounds of the formula (Ib) are formed.

Bothe dextro-rotatory and laevo-rotatory alcohol radicals can be used asthe alcohol components --^(*) OR⁸ in the formula (VI) in process variantc), so that the configuration of the radical --^(*) OR⁸ need not bespecified in more detail in the following text.

The diastereomeric 1,4-dihydropyridine derivatives of the formula (VI)used as starting substances in process variang (c) are known (see DT-OS(German Published Specification) 2,117,571), or they can be prepared byknown methods by reacting corresponding ylidenes with β-aminocrotonicacid esters, the ester radical of which carries an optically activealcohol component.

Examples which may be mentioned are:5-cyano-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3-carboxylicacid α-cyanoethyl ester,5-acetyl-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3-carboxylicacid α-cyanoethyl ester,5-benzoyl-1,4-dihydro-2-methyl-6-phenyl-4-(2'-trifluoromethyl)-pyridine-3-carboxylicacid α-cyanoethyl ester,5-phenylsulphonyl-1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3-carboxylicacid α-methoxycarbonylethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl α-cyanoethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl α-methoxycarbonylethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl α-methoxycarbonylbenzyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl β-methoxy-β-phenyl-ethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl α-cyanoethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl α-methoxycarbonylbenzyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl β-methoxy-β -phenyl-ethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl 2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester,1,4-dihydro-2,6-dimetyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl α-cyanoethyl ester,1,4-dihydro-2,6dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl α-cyanobenzyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl α-methoxycarbonylethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl α-methoxycarbonylbenzyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl β-methoxy-β-phenylethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester,2-[1,4-dihydro-5-(2-propoxycarbonyl)-2,6-dimethyl-4-(3'-nitrophenyl)-3-pyridylcarbonyloxy]-ethylβ-D-glucopyranoside,2-[1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(2'-chlorophenyl)-3-pyridylcarbonyloxy]-ethylβ-D-glucopyranoside,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid methyl α-cyanoethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine- 3,5-dicarboxylicacid isobutyl β-methoxy-β-phenyl-eth 1 ester,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid methyl α-methoxycarbonylethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid methyl β-methoxy-β-phenyl-ethyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-2-yl)-pyridine-3,5-dicarboxylic acidmethyl β-methoxy-β-phenyl-ethyl ester and1,4-dihydro-2,6-dimethyl-4-(pyrid-3-yl)-pyridine-3,5-dicarboxylic acidethyl β-methoxy-β-phenyl-ethyl ester.

As diastereomers, the compounds of the formula (VI) formed according tovariant (c) differ from one another in respect of their physical andchemical properties and can thus be separated from one another with theaid of known methods. Preferred separation methods which may bementioned are: recrystallisation from inert solvents, thin layerchromatography, column chromatography and high performance liquidchromatography.

The separated 1,4-dihydropyridine derivatives of the formula (VII)having a single configuration are moreover suitable as intermediateproducts for the simple preparation of compounds of the formula (Ia) and(Ib) and, in the case where ^(*) R⁸ has the meaning of ^(*) R⁴, arealready valuable pharmacological active compounds. Thetrans-esterification of the compounds (VII) which may be required ispreferably carried out by alkaline alkanolysis, if appropriate in thepresence of an inert additional solvent, using R⁴ -O.sup.⊖ or ^(*) R⁴-O.sup.⊖ as the alcoholic agent, R⁴ and ^(*) R⁴ having the meaningindicated above.

Possible solvents for this trans-esterification are any of the inertorganic solvents or mixtures thereof. These include, as preferences,ethers, such as dioxane, tetrahydrofurane, glycol monomethyl ether orglycol dimethyl ether, or dimethylformamide, dimethylsulphoxide,acetonitrile, pyridine or hexamethylphosphoric acid triamide.

The reaction temperatures can be varied within a substantial range. Ingeneral, the reaction is carried out between 20° and 150° C., preferablyat about 50° to 100° C.

The reaction can be carried out under normal pressure, but also underincreased pressure. In general, it is carried out under normal pressure.

Preferred alcoholysis agents are alkali metal alcoholates, such assodium alcoholates or potassium alcoholates. There are in each caseemployed in molar amounts or in a slight excess in carrying out thealcoholysis.

A further possibility for the last step for process variant (c), asmentioned, consists in first hydrolysing the 1,4-dihydropridinederivatives of the formula (VII) having a single configuration to givethe optically active 1,4-dihydropyridinecarboxylic acids of the formula(IV) having a single configuration, and then esterifying these acids (asdescribed under process variant b) to give the compounds of the formula(Ia) and (Ib) according to the invention.

Preferred possible hydrolysis agents for this hydrolysis are inorganicbases. These include, in particular, alkali metal hydroxides, such assodium hydroxide or potassium hydroxide. The bases can be employed inmolar amounts or in a 2- to 3-fold excess, depending on the nature ofthe organic starting compound.

A large excess of water has proved an advantageous reaction medium. Inorder to carry out the reaction in a homogeneous system, it is as a ruleappropriate to add an inert, water-miscible organic solvent. Thesesolvents include, preferably, alcohols, such as methanol, ethanol orpropanol, ethers, such as dioxane, tetrahydrofurane or1,2-dimethoxyethane, or pyridine, dimethylformamide, dimethylsulphoxideor hexamethylphosphoric acid triamide.

In addition to the preparation examples listed below, the followingoptically active compounds according to the invention may be mentioned:1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pryridine-3,5-dicarboxylicacid methyl ethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl propyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl cyclopentyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2-methoxy-ethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl benzyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2-phenoxyethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2-dimethylaminoethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 2-N-benzyl-N-methylaminoethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl) -pyridine-3,5-dicarboxylicacid methyl ethyl ester, 1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl isopropylester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl cyclopentyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl isobutyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl benzyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl 3-phenoxypropyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl isobutyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid methyl 2,2,2-trifluoroethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-chlorophenyl)-pyridine-3,5-dicarboxylicacid ethyl 2,2,2-trifluoroethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-propoxyethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-phenoxyethyl ester,1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-N-benzyl-N-methylaminoethyl ester,1,4-dihydro-2,6-dimethyl-4 -(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-dimethylaminoethyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylicacid isopropyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-dicarboxylicacid ethyl isopropyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-3-yl)-pyridine-3,5-dicarboxylic acidethyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-3-yl)-pyridine-3,5-dicarboxylic acidisopropyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(pyrid-2-yl)-pyridine-3,5-dicarboxylic acidisopropyl methyl ester1,4-dihydro-2,6-dimethyl-4-(2-chloropyrid-3-yl)-pyridine-3,5-dicarboxylicacid ethyl methyl ester,1,4-dihydro-2,6-dimethyl-4-(2-chloropyrid-3-yl)-pyridine-3,5-dicarboxylicacid ethyl isopropyl ester,1,4-dihydro-2,6-dimethyl-4-(2-methyl-pyrid-3-yl)-pyridine-3,5-dicarboxylicacid ethyl methyl ester and1,4-dihydro-2,6-dimethyl-4-(2-methylthiophenyl-3)-pyridine-3,5-dicarboxylicacid isopropyl methyl ester. These compounds can be preferably preparedaccording to the process (C) analogously to examples 1 and 2.

The compounds according to the invention can be used as medicaments, inparticular as active compounds having an influence on vessels andcirculation. They have a broad and diverse pharmacological actionspectrum. In detail, the following main actions could be demonstrated inanimals experiments:

1. The compounds produce a distinct and long-lasting dilation of thecoronary vessels on parenteral, oral and perlingual administration. Thisaction on the coronary vessels is intensified by a simultaneousnitrite-like effect of reducing the load on the heart.

They influence or modify heart metabolism in the sense of a saving ofenergy.

2. The excitability of the stimulus formation and excitation conductionsystem within the heart is lowered, so that an antifibrillation actionwhich can be demonstrated at therapeutic doses, results.

3. The tone of the smooth muscle of the vessels is greatly reduced underthe action of the compounds. This vascular-spasmolytic action can takeplace in the entire vascular system or can manifest itself more or lessisolated in circumscribed vascular regions, such as, for example, thecentral nervous system, in particular in the cerebral region.

4. The compounds lower the blood pressure of hypertonic animals and canthus be used as antihypertensive agents.

5. The compounds have a powerful muscular-spasmolytic action whichmanifests itself on the smooth muscle of the stomach, intestinal tract,urogenital tract and respiratory system.

On the basis of these properties, the compounds according to theinvention are particularly suitable for the prophylaxis and therapy ofacute and chronic ischaemic heart disease in the broadest sense, for thetherapy of hypertension and for the treatment of disorders in cerebraland peripheral blood flow.

As stated above, the invention also relates to the use in medicine ofthe compounds of the invention.

The present invention provides a pharmaceutical composition containingas active ingredient a compound of the invention in admixture with asolid or liquefied gaseous diluent, or in admixture with an inertpharmaceutical carrier, such as a liquid diluent other than a solvent ofa molecular weight less than 200 (preferably less than 350) expect inthe presence of a surface active agent.

The invention further provides a pharmaceutical composition containingas active ingredient a compound of the invention in the form of asterile and/or physiologically isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprisinga compound of the invention.

The invention also provides a medicament in the form of tablets(including lozenges and granules), dragees, capsules, pills, ampoules orsuppositories comprising a compound of the invention.

"Medicament" as used in this Specification means physically discretecoherent portions suitable for medical administration. "Medicament indosage unit form" as used in this Specification means physicallydiscrete coherent units suitable for medical administration eachcontaining a daily dose or a multiple (up to four times) or submultiple(down to a fortieth) of a daily dose of the compound of the invention inassociation with a carrier and/or enclosed within an envelope. Whetherthe medicament contains a daily dose or, for example, a half, a third ora quarter of a daily dose will depend on whether the medicament is to beadministered once or, for example, twice, three times or four times aday respectively.

The pharmaceutical composition according to the invention may, forexample, take the form of suspensions, solutions and emulsions of theactive ingredient in aqueous or non-aqueous diluents, syrups, granulatesor powders.

The diluents to be used in pharmaceutical compositions (e.g. granulates)adapted to be formed into tablets, dragees, capsules and pills includethe following: (a) fillers and extenders, e.g. starch, sugars, mannitol,and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose andother cellulose derivatives, alginates, gelatine and polyvinylpyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegratingagents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e)agents for retarding dissolution e.g. paraffin; (f) resorptionaccelerators, e.g. quaternary ammonium compounds; (g) surface activeagents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptivecarriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calciumand magnesium stearate and solid polyethyl glycols.

The tablets, dragees, capsules and pills formed from the pharmaceuticalcompositions of the invention can have the customary coatings, envelopesand protective matrices, which may contain opacifiers. They can be soconstituted that they release the active ingredient only or preferablyin a particular part of the intestinal tract, possibly over a period oftime. The coatings, envelopes and protective matrices may be made, forexample, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated form togetherwith one or several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to beformed into suppositories can, for example, be the usual water-soluablediluents, such as polyethylene glycols and fats (e.g. cocoa oil and highesters (e.g. C₁₄ -alcohol with C₁₆ -fatty acid)) or mixtures of thesediluents.

The pharmaceutical compositions which are solutions and emulsions can,for example, contain the customary diluents (with, of course, theabove-mentioned exclusion of solvents having a molecular weight below200 except in the presence of a surface-active agent), such as solvents,dissolving agents and emulsifiers; specific examples of such diluentsare water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (for example ground nut oil), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitol or mixtures thereof.

For parenteral administration, solutions and emulsions should besterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain theusual diluents, such as liquid diluents, e.g. water, ethyl alcohol,propylene glycol, surface-active agents (e.g. ethoxylated isostearylalcohols, polyoxyethylene sorbite and sorbitane esters),microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can alsocontain colouring agents and preservatives as well as perfumes andflavouring additions (e.g. peppermint oil and eucalyptus oil) andsweetening agents (e.g. saccharin).

The pharmaceutical compositions according to the invention generallycontain from 0.5% to 90% of the active ingredient by weight of the totalcomposition.

In addition to a compound of the invention, the pharmaceuticalcompositions and medicaments according to the invention can also containother pharmaceutically active compounds. They may also contain aplurality of compounds of the invention.

Any diluent in the medicaments of the present invention may be any ofthose mentioned above in relation to the pharmaceutical compositions ofthe present invention. Such medicaments may include solvents ofmolecular weight less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according tothe invention will generally be adapted by virtue of their shape orpackaging for medical administration and may be, for example, any of thefollowing: tablets (including lozenges and granulates), pills, dragees,capsules, suppositories and ampoules. Some of these forms may be made upfor delayed release of the active ingredient. Some, such as capsules,include a protective envelope which renders the portions of themedicament physically discrete and coherent.

The preferred daily dose for administration of the medicaments of theinvention is 2.5 mg to 50 mg in the case of intravenous administration,and 5 mg to 250 mg in the case of oral administration of activeingredient.

The production of the above-mentioned pharmaceutical compositions andmedicaments is carried out by any method known in the art, for example,by mixing the active ingredient (s) with the diluent (s) to form apharmaceutical composition (e.g. a granulate) and then forming thecomposition into the medicament (e.g. tablets).

This invention further provides a method of combating theabove-mentioned diseases in warm-blooded animals, which comprisesadministering to the animals a compound of the invention alone or inadmixture with a diluent or in the form of a medicament according to theinvention.

It is envisaged that these active compounds will be administeredperorally, parenterally (for example intramuscularly, intraperitoneally,subcutaneously and intravenously), or rectally, preferably orally orparenterally, especially perlingually or intravenously. Preferredpharmaceutical compositions and medicaments are therefore those adaptedfor administration such as oral or parenteral administration.Administration in the method of the invention is preferably oral orparenteral administration.

In general it has proved advantageous to administer amounts of from0.001 mg to 10 mg/kg, preferably 0.05 mg to 1 mg/kg of body weight perday in the case of intravenous administration and 0.05 mg to 20 mg,preferably 0.1 to 5 mg/kg of body weight per day in the case of oraladministration, to achieve effective results. Nevertheless, it can attimes be necessary to deviate from those dosage rates, and in particularto do so as a function of the nature and body weight of the human oranimal subject to be treated, the individual reaction of this subject tothe treatment, the type of formulation in which the active ingredient isadministered and the mode in which the administration is carried out,and the point in the progress of the disease or interval at which it isto be administered. Thus it may in some case suffice to use less thanthe above-mentioned minimum dosage rate, whilst other cases the upperlimit mentioned must be exceeded to achieve the desired results. Wherelarger amounts are administered it can be advisable to divide these intoseveral individual administrations over the course of the day.

The optical purity of the compounds of the formulae (Ia) and (Ib)obtained by the following preparation examples and of the particularstarting materials and intermediate products was examined and confirmedby proton resonance spectroscopy, by addition of (chiral) lanthanideshift agents.

The following Preparative Examples illustrate the preparation ofcompounds of the present invention.

Preparative Examples (according to process variant (c))

(A) Preparation of(+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxy-2-phenylethyl ester (compound A) ##STR8##

A solution of 14.5 g (96 mmols) of 3-nitrobenzaldehyde, 13.7 g (96mmols) of β-aminocrotonic acid isopropyl ester and 22.8 g (96 mmols) ofacetoacetic acid 2-methoxy-2-phenylethyl ester in 150 ml of isopropanolis heated to the boiling point under nitrogen for 12 hours.

The solvent is then distilled off in vacuo and the oily residue istriturated with a little ether, whereupon the reaction product partlysolidified. The crystals which has precipitated was filtered off andrecrystallised from ethanol. Melting point: m.p. =173° C., yield: 19 g(40%)

This crystalline fraction is a single configuration and the specificoptical rotation [α]_(D) ²⁰ =+53.82° (c=1,1% w/v^(*), ethanol)

(B) Preparation of(-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxy-2-phenylethyl ester (compound (b) ##STR9##

A solution of 27.7 g (0.1 mol) of 3'-nitrobenzylideneacetoacetic acidisopropyl ester and 23.5 g (0.1 mol) of β-aminocrotonic acid2-methoxy-2-phenyl-ethyl ester in 160 ml of methanol is heated to theboiling point under nitrogen for 12 hours. The solvent is then distilledoff in vacuo and the oily residue is triturated with a little ether. Thereaction product thereby solidified and is filtered off andrecrystallised from ethanol.

Melting point: m.p. =173° C., yield: 11.8 (24%)

The product has a single configuration and the specific optical rotation[α]_(D) ²⁰ =-53.3° (c=1.04% w/v, ethanol).

Example 1(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl methyl ester ##STR10##

19 g (38 mmols) of(+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxy-2-phenylethyl ester (compound A) in a solutionof 0.87 g (38 mmols) of sodium in 50 ml of methanol and 50 ml of1,2-dimethoxyethane are heated to the boiling point under nitrogen for 5hours. The solution is then concentrated to half the volume in vacuo andacidified with dilute hydrochloric acid. After adding an equal part ofwater, the mixture is extracted several times with methylene chlorideand the extracts are concentrated in vacuo, after drying over sodiumsulphate. The solid residue is recrystallized from methanol (crudeyield: 5.5 g (3.%), melting point: 134°-136° C.) and the product is thenpurified by high performance liquid chromatography on a preparative RP8column (10μ), internal diameter 16 mm, length 250 mm, usingacetonitrile/water =45/55 as the eluting agent.

Melting point: m.p. =136° C.

Specific optical rotation: [α]_(D) ²⁰ =+24.97 (c=0.93% w/v, ethanol).

Example 2(-)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl methyl ester ##STR11##

16.5 g (33.4 mmols) of(-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxy-2-phenylethyl ester (compound B) in a solutionof 0.87 g (38 mmols) of sodium in 100 ml of methanol are heated to theboiling point under nitrogen for 24 hours. After cooling, the solutionis concentrated to about half the volume in vacuo and acidified withdilute hydrochloric acid. After adding an equal part of water, themixture is extracted several times with methylene chloride and theextracts are concentrated in vacuo, after drying over sodium sulphate.The residue crystallized completely and is filtered off andrecrystallized from methanol (crude yield: 4.2 g (34%), melting point:132°-134° C.), and the product is purified by high performance liquidchromatography, as described under Example 1.

Melting point: m.p. =136° C.

Specific optical rotation: [60 ]_(D) ²⁰ =-24.60° (c =1.07% w/v,ethanol).

Example 3(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl isopropyl ester ##STR12##

19 g (38 mmols) of(+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-carboxylicacid isopropyl 2-methoxy-2-phenylethyl ester (compound A) in a solutionof 0.87 g (38 mmols) of sodium in 100 ml of ethanol are heated to theboiling point under nitrogen for 8 hours. The solvent is then distilledoff in vacuo, the residue is taken up in water and the mixture isacidified with dilute hydrochloric acid and extracted several times withmethylene chloride. The extracts are concentrated in vacuo, after dryingover sodium sulphate. The residue crystallised completely and isfiltered off and recrystallised from methanol (crude yield: 4.1 g (2,%),melting point: 143°-146° C.), and the product is purified by highperformance liquid chromatography, as described under

Example 1.

Melting point: m.p. =140° C.

Specific optical rotation: [α]_(D) ²⁰ =+4.61 (c =0.46% w/v, ethanol).

Example 4(-)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl isopropyl ##STR13##

18.6 g (27.6 mmols) of(-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxy-2-phenylethyl ester (compound (B) in a solutionof 0.86 g (3m.6 mmols) of sodium in 100 ml of ethanol are heated to theboiling point under nitrogen for 8 hours. The solution is thenconcentrated to about half the volume in vacuo, acidified with dilutehydrochloric acid and, after adding an equal part of water, extractedseveral times with methylene chloride. The extracts are concentrated invacuo, after drying over sodium sulphate. The residue initially obtainedas an oil soon crystallized completely and is filtered off andrecrystallised from methanol (crude yield: 2.8 g (19,2%), melting point:146°-149° C.), and the product is purified by high performance liquidchromatography, as described under

Example 1.

Melting point: m.p. =140°

Specific optical rotation: [α]_(D) ²⁰ =-4.75 (c =0.51% w/v, ethanol).

Example 5(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxyethyl ester ##STR14## 24.7 g (50 mmols) of(+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl-2-methoxy-2-phenylethyl ester (compound A) are stirred ina solution of 1.4 g (61 mmols) of sodium in 230 ml of freshly distilledglycol monomethyl ether at 85° C. under nitrogen for 8 hours. Aftercooling, the solvent is distilled off in vacuo, the residue is taken upin water and the mixture is acidified with dilute hydrochloric acid andextracted several times with methylene chloride. The organic extractsare concentrated, after drying over sodium sulphate, and the oilyresidue is triturated with a little ether, where-upon the substancerapidly crystallizes completely. The solid reaction product is filteredoff (crude

yield: 15.1 g (72%),

melting point: 126°-129° C.) and recrystallized twice from ethanol.

Melting point: m.p. =134° C.

Specific optical rotation: [α]_(D) ²⁰ =+17.10° (c==0.96% w/v, ethanol).

Example 6(-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl 2-methoxyethyl ester ##STR15##

8.2 g (16.6 mmols) of(-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid isopropyl-2-methoxy-2-phenylethyl ester (compound B) are stirred ina solution of 0.5 g (21.8 mmols) of sodium in 80 ml of freshly distilledgylcol monomethyl ether at 85° C. under nitrogen for 8 hours. Aftercooling, the solvent is distilled off in vacuo, the residue is taken upin water and the mixture is acidified with dilute hydrochloric acid andextracted several times Le A 19 861 with methylene chloride. The organicextracts are concentrated, after drying over sodium sulphate. The oilyresidue soon crystallizes completely and, after adding a little ether,is filtered off (crude yield: 5.1 g (73%)) and recrystallized twice fromethanol.

Melting point: m.p. =134° C.

Specific optical rotation: [α]_(D) ²⁰ =-16.9 (c=1.5% w/v, ethanol).

Example 7(-)-1,4dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl methyl ester ##STR16## 7,5 g (16 mmoles) of(-)-1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylicacid ethyl 2-(S)-methoxy-2-phenylethyl) ester (compound B) in a solutionof 0,41 g (18 mmoles) of sodium in 75 ml of methanol heated to theboiling point under nitrogen for 5 hours. The solvent is then distilledoff in vacuo, the residue is taken up in water and the mixture isacidified with dilute hydrochloride acid and extracted several timeswith methylene chloride. The organic extracts are concentrated in vacuo,after drying over sodium sulphate. The only residue crystallisedcompletely (crude yield: 3,5 g) and the product is then purified byhigher performance liquid chromatography as described in example 1.

Melting point: m.p. =159°-160° C.

Specific optical rotation [α]_(D) ²⁰ =-15.02° C. (c=0,49 w/v, ethanol).

Example 8(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)pyridine-3,5-dicarboxylicacid isobutyl methyl ester ##STR17## is obtained analogeously to themethod described in example 7 by selective alcoholyse of the compond ofthe formula D by using isobutanole.

Melting point: m.p. =138° C.

Specific optical rotation: [α]_(D) ²⁰ =+25,9° C. (c=0.50 ethanol)

Example 9

The compound(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylicacid methyl neopentyl ester of the formula ##STR18## is obtainedanalogeously to the method described in example 7 by selectivealcoholyse of the compound of the formula D with neopentyl alcohol.

Melting point: m.p. =131° C.

Specific optical rotation: [α]^(D) ²⁰ =+53.4° (c=0,51 ethanol

Example 10

The compound(=)-1,4-Dihydro-2,6-dimethyl-4-(2'-nitriphenyl)-pyridine-3,5-dicarboxylicacid isobutyl methyl ester of the formula ##STR19## is obtained as ayellowish oil which builds an amorpheous product after drying in vacuo.Specific optical rotation: [α]_(D) ²⁰ =+165.93° C. (c=0,512, ethanol).

Among the new optically active 1,4-dihydro-pyridine salts of theinvention, those salts that are pharmaceutically acceptable areparticularly important and are preferred.

The new free optically active 1,4-dihydro-pyridine compounds of thegeneral formula (Ia) and their salts can be interconverted in anysuitable manner; methods for such interconversion are known in the art.

The present invention also comprises pharmaceutically acceptablebioprecursors of the active compounds of the present invention.

For the purpose of this specification the term pharmaceuticallyacceptable bioprecursor` of an active compound of the invention means acompound having a structural formula different from the active compoundbut which nonetheless, upon administration to a warm-blooded animal isconverted in the patient's body to the active compound.

What is claimed is:
 1. The compound (+)-1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl isobutyl ester.
 2. A pharmaceutical composition comprising, as an active ingredient, a coronary dilator effective amount of a compound according to claim 1 in admixture with an inert pharmaceutical carrier.
 3. A pharmaceutical composition of claim 2 in the form of a sterile or physiologically isotonic aqueous solution.
 4. A composition according to claim 2 or 3 containing from 0.5 to 90% by weight of the said active ingredient.
 5. A medicament in dosage unit form comprising an amount of a compound according to claim 1 as a coronary dilator together with an inert pharmaceutical carrier.
 6. A medicament of claim 5 in the form of tablets, pills, dragees, capsules, ampoules or suppositories.
 7. A method of effecting coronary dilation in warm-blooded animals which comprises administering to the animals a coronary dilation influencing amount of an active compound according to claim 1 either alone or in admixture with an inert pharmaceutical carrier or in the form of a medicament.
 8. A method according to claim 7 in which the active compound is administered intravenously in an amount of 0.05 to 1 mg per kg body weight per day.
 9. A method according to claim 7 in which the active compound is administered orally in an amount of 0.1 to 5 mg per kg body weight per day. 